Methods and compositions for preparing and purifying noribogaine

ABSTRACT

Disclosed are methods and compositions for purifying the non-addictive alkaloid noribogaine.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §119(e) to U.S.Provisional Patent Application Ser. No. 61/333,476, filed on May 11,2010, and to U.S. Provisional Patent Application Ser. No. 61/419,772,filed on Dec. 3, 2010, both of which applications are incorporated byreference herein in their entirety.

FIELD OF THE INVENTION

This invention relates generally to methods and compositions forpurifying the non-addictive alkaloid noribogaine.

STATE OF THE ART

Noribogaine is a well known derivative of ibogaine and is sometimesreferred to as 12-hydroxyibogaine. It is a metabolite of ibogaine. U.S.Pat. No. 2,813,873 claims noribogaine albeit as “12-O-demethylibogaine”while providing an incorrect structural formula for ibogaine. Thestructure of noribogaine has now been thoroughly evaluated and is foundto combine the features of tyrptamine, tetrahydrohavaine andindolazepines. Noribogaine can be depicted by the following formula:

Noribogaine and its pharmaceutically acceptable salts have recentlyreceived significant attention as a non-addictive alkaloid useful intreating drug dependency (U.S. Pat. No. 6,348,456) and as a potentanalgesic (U.S. Pat. No. 7,220,737).

Conventionally, noribogaine is prepared by demethylation of naturallyoccurring ibogaine:

which is isolated from Tabernanth iboga, a shrub of West Africa.Demethylation may be accomplished by conventional techniques such as byreaction with boron tribromide/methylene chloride at room temperaturefollowed by conventional purification.

Ibogaine possesses hallucinogenic properties. It is a Schedule1-controlled substance as provided by the US Food and DrugAdministration. Accordingly, methods for preparing noribogaine fromibogaine require high levels of assurance that contamination withunacceptable levels of ibogaine is avoided. As above, a one-step methodfor preparation of noribogaine from ibogaine via demethylation does notprovide the requisite assurance that ibogaine will consistently beremoved as a potential contaminant.

Accordingly, there is an ongoing need to provide a method for preparingnoribogaine from ibogaine wherein any ibogaine contamination ofnoribogaine can be effectively and repeatedly minimized.

SUMMARY OF THE INVENTION

This invention provides methods and compositions for the preparation ofnoribogaine wherein contamination by ibogaine is predictably reduced toacceptable levels. In particular, this invention employs the use ofsolid supports to effect separation of noribogaine from ibogaine suchthat any ibogaine contamination is significantly reduced if notessentially eliminated.

Accordingly, in one of its method aspects, this invention is directed toa method for preparing and purifying noribogaine which method comprises:

a) converting ibogaine to noribogaine wherein the indole nitrogen isoptionally protected by an amino protecting group;

b) covalently attaching noribogaine to a solid support via the hydroxylgroup of noribogaine so as to form a suspension of solid supports havingnoribogaine bound thereto;

c) removing residual ibogaine from said suspension;

d) cleaving and recovering noribogaine from the solid support; and

e) optionally repeating steps b), c) and d) up to 5 times;

f) purifying noribogaine as recovered per above.

In another of its method aspects, this invention is directed to a methodfor preparing and purifying noribogaine which method comprises:

a) covalently attaching ibogaine to a solid support via the amino groupof ibogaine so as to form a suspension of solid supports having ibogainebound thereto;

b) converting ibogaine to noribogaine under conditions wherein the levelof ibogaine bound to the solid support is less than 0.1 weight percent;

c) cleaving and recovering noribogaine from the solid support; and

d) purifying noribogaine as recovered per above.

In one of its composition aspects, this invention is directed to a solidsupport having ibogaine or noribogaine covalently bound thereto througha cleavable linker

In one embodiment, the solid support of this invention comprisesibogaine covalently bound thereto through a cleavable linker. In anotherembodiment, the solid support of this invention comprises noribogainecovalently bound thereto through a cleavable linker.

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to methods and compositions comprisingnoribogaine and, in particular, methods and compositions comprisinghighly pure noribogaine. However, prior to describing this invention ingreater detail, the following terms will first be defined.

It is to be understood that this invention is not limited to particularembodiments described, as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting, since the scope of the present invention will be limited onlyby the appended claims.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “apharmaceutically acceptable excipient” includes a plurality of suchexcipients.

1. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. As used herein the followingterms have the following meanings.

As used herein, the term “comprising” or “comprises” is intended to meanthat the compositions and methods include the recited elements, but notexcluding others. “Consisting essentially of” when used to definecompositions and methods, shall mean excluding other elements of anyessential significance to the combination for the stated purpose. Thus,a composition consisting essentially of the elements as defined hereinwould not exclude other materials or steps that do not materially affectthe basic and novel characteristic(s) of the claimed invention.“Consisting of” shall mean excluding more than trace elements of otheringredients and substantial method steps. Embodiments defined by each ofthese transition terms are within the scope of this invention.

The term “about” when used before a numerical designation, e.g.,temperature, time, amount, and concentration, including range, indicatesapproximations which may vary by (+) or (−) 10%, 5% or 1%.

As stated above, the invention is directed to compositions comprisingnoribogaine and an excipient to facilitate transport across the bloodbrain barrier.

As used herein, the term “noribogaine” refers to the compound:

and salts thereof. Conventionally, noribogaine is prepared bydemethylation of naturally occurring ibogaine:

which is isolated from Tabernanth iboga, a shrub of West Africa.Demethylation may be accomplished by conventional techniques such as byreaction with boron tribromide/methylene chloride at room temperature,or reaction with lithium diphenylphosphine (preferably an excessthereof), followed by conventional purification. This invention is notlimited to any particular chemical form of noribogaine and the compoundmay be present as either as a free base or as an acceptable additionsalt.

The term “solid support” refers to a material having a rigid orsemi-rigid surface which contain or can be derivatized to containreactive functionality which covalently links noribogaine or ibogaine tothe surface thereof through a cleavable linker. Such materials are wellknown in the art and include, by way of example, silica, syntheticsilicates, biogenic silicates, porous glass, hydrogels,silicate-containing minerals, synthetic polymers, polystyrene,polypropylene, polyacrylamide, polyethylene glycol, polyacrylamide andcopolymers thereof including copolymers of polystyrene/polyethyleneglycol and polyacrylamide/polyethylene glycol, and the like.

As used herein, the term “ion exchange resin” refers to an insolubleorganic polymer containing charged groups that attract and holdoppositely charged ions present in a surrounding solution in exchangefor counterions previously held. Suitable ion exchange resins to be usedherein contain cationic groups that attract and hold anions present in asurrounding solution, and are sometimes referred to as “anion exchangeresins”.

As used herein, the term “cleavable linking arms” refers to linkingarms, which are a chemical group or a covalent bond which covalentlyattaches at one end to a solid support and at the other end to ibogaineor noribogaine. At least one of the covalent bonds of the linking armwhich attaches ibogaine or noribogaine to the solid support can bereadily broken by specific chemical or enzymatic reactions, therebyproviding for ibogaine or noribogaine free of the solid support. Thechemical or enzymatic reactions employed to break the covalent bond ofthe linking arm are selected so as to be specific for bond breakagethereby preventing unintended reactions occurring elsewhere on thecompound. The cleavable linking group is selected relative toibogaine/noribogaine formed on the solid support so as to preventpremature cleavage of either ibogaine or noribogaine from the solidsupport as well as not to interfere with any of the procedures employedduring synthesis on the support. Suitable cleavable linking arms arewell known in the art, and may include such groups as carbonate groups,carbamate groups, amide groups, and the like. In a preferred embodiment,the cleavable linker arm contains no more than 10 atoms. Morepreferably, the cleavable linker contains from 1 to 4 carbon atoms andfrom 2 to 4 heteroatoms selected from oxygen, nitrogen, sulfur, S(O) andS(O)₂.

As used herein, the term “an acceptable addition salt” refers topharmaceutically acceptable salts of a compound of Formula I which saltsare derived from a variety of organic and inorganic counter ions wellknown in the art and include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe molecule contains a basic functionality, salts of organic orinorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like.

As used herein, the term “protecting group” or “Pg” refers to well knownfunctional groups which, when bound to a functional group, render theresulting protected functional group inert to the reaction conditions tobe conducted on other portions of the compound and which, at theappropriate time, can be reacted to regenerate the originalfunctionality. The identity of the protecting group is not critical andis selected to be compatible with the remainder of the molecule. In oneembodiment, the protecting group is an “amino protecting group” whichprotects the amino functionality of ibogaine or noribogaine during thereactions described herein. Examples of conventional amino protectinggroups include, for instance, benzyl, acetyl, oxyacetyl, carboxybenzyl(Cbz), and the like. In another embodiment, the protecting group is a“hydroxy protecting group” which protects the hydroxyl functionality ofnoribogaine. Examples of hydroxyl protecting groups include, forinstance, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl, trityl,dialkylsilylethers, such as dimethylsilyl ether, and trialkylsilylethers such as trimethylsilyl ether, triethylsilyl ether, andt-butyldimethylsilyl ether; esters such as benzoyl, acetyl,phenylacetyl, formyl, mono-, di-, and trihaloacetyl such aschloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl; andcarbonates such as methyl, ethyl, 2,2,2-trichloroethyl, allyl, benzyl,and p-nitrophenyl. Additional examples of hydroxy protecting groups maybe found in standard reference works such as Greene and Wuts, ProtectiveGroups in Organic Synthesis., 2d Ed., 1991, John Wiley & Sons, andMcOmie Protective Groups in Organic Chemistry, 1975, Plenum Press.

Preparation and Purification of Noribogaine

The compounds of this invention can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in T. W. Greene and G. M. Wuts, Protecting Groups in OrganicSynthesis, Fourth Edition, Wiley, N.Y., 2007, and references citedtherein.

Furthermore, the compounds of this invention will typically contain oneor more chiral centers. Accordingly, if desired, such compounds can beprepared or isolated as pure stereoisomers, i.e., as individualenantiomers or diastereomers, or as stereoisomer-enriched mixtures. Allsuch stereoisomers (and enriched mixtures) are included within the scopeof this invention, unless otherwise indicated. Pure stereoisomers (orenriched mixtures) may be prepared using, for example, optically activestarting materials or stereoselective reagents well-known in the art.Alternatively, racemic mixtures of such compounds can be separatedusing, for example, chiral column chromatography, chiral resolvingagents and the like.

It is contemplated that noribogaine can be prepared and/or purified fromibogaine by utilizing solid support as shown in the following Schemes,where PG represents an amine protecting group, LG represents a leavinggroup (e.g. a halo or alcohol), L represents a cleavable linking group(e.g. a carbonyl compound such as a carbonate or carbamate) and theshaded circle represents a solid support. In the following Schemes, theO-demethylation of the aryl methoxy group to provide the correspondingphenol can be accomplishing using any suitable method known in the art.Suitable reagents include a Lewis acid (e.g. BBr₃, AlCl₃), a nucleophile(e.g. RS—, N₃—, SCN—), NaCN at low pH (e.g. pH 12), lithiumdiphenylphosphine (preferably an excess thereof), and the like. In someembodiments, the O-demethylation should be performed without affectingthe linkage to the solid support. Suitable reagents can be readilyascertained by one of skill in the art and can be found, for example, inT. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis,Fourth Edition, Wiley, N.Y., 2007 (see, e.g., the reactivity charts atpages 1006-1008 and 1022-1032), and references cited therein.

Noribogaine 5 can be prepared and purified from ibogaine 10 by any oneof the routes shown in Scheme 1. Noribogaine, compound 5, isdifferentiated from ibogaine by virtue of the fact that the methoxygroup of ibogaine has been converted to a hydroxyl group in noribogaine.In one embodiment, the indole amine of ibogaine can be protected usingan amine protecting group to provide compound 1, followed by eithertandem O-demethylation and removal of the protecting group usingL-selectride®, for example, or sequential O-demethylation and removal ofthe protecting group to provide noribogaine 5. In addition, in oneembodiment, noribogaine can be directly prepared and purified from theO-demethylation of ibogaine using methods known in the art and thenpurified by appending noribogaine to a solid support (compound 12 or13), washing any contaminants, cleaving the linking group L, andrecovering the noribogaine 5. In the above syntheses, one or more of thenoribogaine or intermediates shown above can be purified using standardpurification techniques known in the art (e.g. column chromatography,HPLC, and the like). Compounds of formula II are commercially availableor can be synthesized in one or two steps from commercially availablestarting materials (see, e.g. commercially available resins fromSigma-Aldrich®).

In one preferred embodiment, purification techniques can be used tomaximize the purity of the recovered noribogaine. In one embodiment,noribogaine can be contacted with a suitable ion exchange resin at a pHwhere the phenol group has deprotonated to a sufficient degree such thatthese compounds are suitable for purification. Typically for phenoldeprotonation, a pH of 10 or greater is used. As ibogaine does not havean ionizable phenolic group, it will not bind to the ion exchange resinand can thus be eluted from column and separated from the resin-boundnoribogaine. Suitable ion exchange resins are commercially available andinclude Amberlite®, Toyopearl®, Lewatit®, Dowex®, Diaion™, andAmberlyst®(Sigma Aldrich, Inc.)

Accordingly, in one of its composition aspects, there is provided anaqueous solution having a pH of at least 10 and a compound of theformula:

The purification process typically comprises pretreating or washing theresin with a solvent system which has the same pH, and other componentssuch buffers, stabilizers, etc., that will be used to dissolve thenoribogaine or salt thereof (“wash solvent”). Washing preferablyincludes passing at least 1 void volume (the volume of solvent needed tofill the resin vessel) of the wash solvent through the resin underambient conditions. Subsequently, noribogaine is added to the samesolvent system used as the wash solvent at a concentration preferablyless than the saturation concentration for noribogaine. Noribogaine maybe present as the phenolic anion under these conditions and,accordingly, both will bind to the anion exchange resin while othercompounds lacking an anionic charge (i.e. ibogaine) will pass throughthe resin. Elution of the purified noribogaine can be then beaccomplished using a cation-containing solution.

Accordingly, in another of its composition aspects, there is provided ananion exchange resin comprising an aqueous solvent system and a pH of atleast 10 and either compound 2a or compound 4a bound thereto.

In one embodiment, noribogaine can be prepared and purified fromibogaine in the manner described in Scheme 2 below:

wherein Pg is hydrogen or an amino protecting group and the shadedcircle represents a solid support.

Specifically, in Scheme 2, amino protected ibogaine, compound 1, iscontacted with boron tribromide in methylene chloride or lithiumdiphenylphosphine using conditions well known in the art to provide forthe amino protected noribogaine, compound 2.

In Scheme 2, attachment of amino protected noribogaine, compound 2, to asolid support is accomplished by use of a chloroformate/solid support,compound 3, under conventional conditions to provide for compound 4wherein the carbonate group is shown for illustrative purposes only asthe cleavable linking group. Other cleavable linkers can likewise beused in Scheme 2. As amino protected ibogaine does not contain afunctional group reactive with compound 3, only amino protectednoribogaine, compound 2, will react with the solid support and providefor compound 4. Repeated washing of compound 4 will remove aminoprotected ibogaine contaminating the sample of amino protectednoribogaine used in this reaction. Furthermore, at any time, a smallportion of the solid support can be removed to provide a sample ofnoribogaine (after cleavage and deprotection). The sample can then beanalyzed for purity relative to any ibogaine present by conventionalmethods such as GC/MS, NMR, C¹³-NMR, etc.

Upon achieving the desired level of purity of noribogaine relative toany contaminating ibogaine, noribogaine, compound 5, can be recoveredfrom the solid support by cleavage of the cleavable linker andsubsequent deprotection of the amino group. Both cleavage anddeprotection are well known in the art.

As desired, exceptionally pure noribogaine, compound 5, can be obtainedby repeating the process of forming the amino protected noribogaine,compound 2, binding compound 2 to a solid support via the hydroxyl groupof amino protected noribogaine and washing any contaminating ibogainefrom the solid support. By repeating this process as often as necessaryand preferably no more than 5 times, it is contemplated that noribogainehaving less than 5 ppm ibogaine and preferably less than 100 pptibogaine can be prepared.

In another embodiment, noribogaine can be prepared and purified fromibogaine in the manner described in Scheme 3 below:

In Scheme 3, ibogaine, compound 10, is bound via conventional techniquesto a solid support, compound 11, through a cleavable linker arm which,for the sake of illustration only, is depicted as a carbamate bond inresulting compound 12. Compound 12 is then contacted with borontribromide in methylene chloride or lithium diphenylphosphine usingconditions well known in the art to provide for the noribogaine boundvia the indole nitrogen to a solid support, compound 13. Cleavage of thecleavable linker in compound 13 provides for noribogaine, compound 5. Incertain embodiments, compound 5 can be directly obtained from compound12 using a reducing agent (e.g. L-Selectride®). See U.S. Pat. No.6,291,675.

In one embodiment, compound 5 can be purified by conventional techniquesincluding high performance liquid chromatography (HPLC) and the puritylevel of the resulting purified compound confirmed by GC/MS.Alternatively, compound 5 can be used in Scheme 2 as recited above byattaching a solid support to the hydroxyl functionality. In either case,very high levels of noribogaine purity can be obtained.

The following synthetic and biological examples are offered toillustrate this invention and are not to be construed in any way aslimiting the scope of this invention. Unless otherwise stated, alltemperatures are in degrees Celsius.

EXAMPLES

In the examples below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning

Example 1 Synthesis and Purification of Noribogaine from Ibogaine

Example 1 illustrates one method for the synthesis and purification ofnoribogaine from ibogaine which method follows Scheme 4 below:

Specifically, in Scheme 4, ibogaine is contacted with a stoichiometricexcess of benzyl chloroformate in an inert solvent such as methylenechloride. The reaction mixture further contains at least astoichiometric equivalent of diisopropylethylamine relative to ibogaineso as to scavenge the acid generated during the reaction. The reactionis maintained at room temperature under an inert atmosphere until thereaction is substantially complete as evidenced by, for example, thinlayer chromatograpy. At which time, an O-demethylation reagent (e.g.boron tribromide, aluminum trichloride, or lithium diphenylphosphine),or preferably a stoichiometric excess thereof, is added to the reactionmixture which is then maintained under conditions (e.g. roomtemperature) wherein the methoxy group of ibogaine has been converted tothe hydroxyl group of noribogaine.

The hydroxyl group generated above is then employed as a complementaryfunctionality for attachment of a solid support. In particular, anexcess of chloroformate bound to a solid support is combined withN-CBZ-noribogaine under conventional conditions wherein a cleavablecarbonate bond is formed. Chloroformate bound to a solid support can beprepared from a hydroxy-bearing polymer support (e.g. hydroxymethyl)polystyrene or polymer-bound benzyl alcohol, both commercially availablefrom Sigma-Aldrich®) and carbonyl dichloride. As CBZ-ibogaine does notreadily react under these O-demethylation conditions, it will remain inthe solution phase of the reaction mixture and can be washed from thereaction mixture by conventional techniques including placing the solidsupport into a column and passing excess solvent through the column.

In one particular example, 1 kg of solid support containingCBZ-noribogaine is loaded onto a column. The stopper of the column ispartially opened so that a flow rate through the column of 0.5 litersper hour is maintained. Methylene chloride is continuously fed to thetop of the column and recovered at the base of the column. The recoveredmethylene chloride is stripped to provide residual CBZ-ibogaine. Theprocess is continued until the effluent from the column no longercontains CBZ-ibogaine. At which time, a portion of the solid support isloaded into a hydrogenation vessel together with methanol and acatalytic amount of palladium on carbon. Hydrogenation is continuedunder elevated pressure for approximately 5 hours. The reaction is thenstopped and the methanol recovered and stripped to provide fornoribogaine. Additional purification of noribogaine can be achieved byHPLC as desired.

What is claimed is:
 1. An ion exchange resin having noribogaineionically bound thereto through an anion of noribogaine's 12-hydroxyfunctional group.